Abstract Direct reversion of cancers into normal tissues is an ideal strategy for cancer treatment. The goal of this proposal is to develop a novel reprogramming method that uses a conceptually unique strategy to reprogram Glioblastoma multiforme (GBM) cells into ?normal? neurons. Reprogramming and oncogenic transformation are stepwise processes that share many similarities. The tumor suppressor p53 is considered today the most important tumor suppressor protein in humans and it suppresses both reprogramming and oncogenic transformation. p53 is often mutations and inactivation in GBMs. Previously we have demonstrated that the depletion of p53 efficiently reprograms human somatic cells into neurons by regulation of a set of transcription factors and found two kinase inhibitors are sufficient to reprogram GBM cells into progenitors and ?normal? neurons under defined culture condition. In vitro and in vivo tumorigenesis assays showed that these induced neurons lose tumorigenicity. Moreover, induced progenitors are sensitive to radiation treatment and ROCK- mTOR inhibitor reprogramming prevents GBM local recurrence in mice. In the proposed project, we will reprogram various p53 deficient GBM cells into progenitors and ?normal? neurons in vitro and in vivo, and develop a novel strategy to combine reprogramming and conventional therapy (radio- and chemo-therapy) to treat GBM. In Aim 1, we will reprogram p53 deficient GBM cells into neurons by targeting mutant and wild-type p53 GBM cells. In Aim 2, we will develop novel reprogramming-based therapy for p53 deficient GBM xenografts in mice. In Aim 3, we will delineate mechanisms of GBM reprogramming. Thus, these studies will allow us to develop a novel reprogramming therapy for GBM treatment, to understand the reprogramming mechanism and to examine feasibility towards clinical trials.